The overall goals of the Program Project are to gain an increased understanding of the mechanisms of photodynamic therapy (PDT) and to optimize treatment parameters. This will be achieved through the following individual research projects: 1. New, congeneric series of photosensitizers will be prepared and characterized, in order to elucidate those parameters which are important for optimal activity and those which are irrelevant. Quantitative data will be obtained which allow use of multi-dimensional QSAR models, and the predictive value of these models will be examined. The relationship between effective sensitizers and their ability to bind to specific intracellular sites will be examined. 2. The kinetics and tissue distributions of certain cytokines which are induced in vivo by PDT via oxidative stress mechanisms will be explored. The hypotheses that these cytokines can, at least in part, account for the immunopotentiating as well as immunosuppressive effects of PDT will be examined. 3. The questions of whether intracellular binding sites of effective photosensitizers are primarily mitochondrial and if the peripheral benzopdiazepine receptor in this organelle is important in sensitizer binding will be explored. The hypothesis that mitochondrial and PBR- associated sensitizers are important in inducing photodamage and the physiological responses which lead to cell death will be explored. 4. Surrogate variables which will provide real-time and short-term information on the underlying mechanistic processes and probably outcomes in clinical PDT and permit tailoring of the therapy to individual patients and lesions will be developed. As a general paradigm, light dose and dose rate effects will be explored in ALA-PDT with different ALA application times in basal cell carcinomas and cutaneous lymphomas, with examination of the photochemical and biological processes contributing to differences in efficacy, efficiency and selectivity. The Program will be supported by three important technical Core components and an Administrative Core.